Voltage-gated sodium (Nav) channels are present in neurons and excitable tissues where they contribute to processes such as membrane excitability and muscle contraction (Ogata et al., Jpn. J. Pharmacol. (2002) 88(4) 365-77). Nine different transmembrane α-subunits (Nav1.1-1.9) from a single Nav1 family combine with auxiliary β-subunits that modify channel function to form functional Nav channels. Of the nine Nav1 α-subunit isoforms, five are expressed in the dorsal root ganglion where they are involved in setting the resting membrane potential and the threshold for generating action potentials, and also contribute to the upstroke as well as firing of action potentials during sustained depolarization. In particular, the tetrodotoxin (TTX) sensitive Nav1.7 and TTX-insensitive Nav1.8 channel subtypes act as major contributors to both inflammatory and neuropathic pain (Momin et al., Curr Opin Neurobiol. 18(4):383-8, 2008; Rush et al., J Physiol. 579(Pt1):1-14, 2007).
Novel allosteric modulators of voltage-gated ion channels (e.g., sodium channels) are thus desired. Modulators may affect the kinetics and/or the voltage potentials of, e.g., Nav1.7 and/or Nav1.8 channels.